Type I diabetes represents about 5-10% of all diabetes cases and occurs as a result of destruction of the pancreatic beta cells, which produce the hormone insulin, by the body's own immune system. The patients are completely dependent on insulin treatment for survival. Type II diabetes is more common (90-95% of all cases). It starts as insulin resistance particularly in the cells of liver, muscle, and adipose tissue that become resistant to the effects of insulin in stimulating glucose and lipid metabolism. As the disease progresses the pancreas gradually loses its ability to produce insulin and if not properly controlled with medication it may lead to pancreatic β-cell failure requiring complete dependence on insulin. While there are five different categories of Type II diabetes medications, they may be ineffective and/or cause undesirable adverse effects such as hypoglycemia, gastrointestinal disturbances, lactic acidosis, weight gain, edema, and anemia.
There continues to be a need to introduce new effective treatments that may be used less frequently, preferably causing fewer side effects and can act either by increasing the endogenous insulin secretion or independently from the actions of insulin.
Prostanoid receptors consist of EP, FP, IP, TP and DP receptors. The EP receptor family is divided into four distinct subtypes EP1, EP2, EP3 and EP4. The EP3 receptor is a 7-transmembrane G-protein coupled receptor found in various human tissues including the kidney, uterus, bladder, stomach and brain. Prostaglandin E2 (PGE2), a primary product of arachidonic acid metabolism by the cyclooxygenase pathway, is the natural ligand of EP3 as well as other EP receptor subtypes. Clinical studies have provided strong evidence of the role of increased levels of PGE2 as a contributor to defective insulin secretion in diabetic patients. Recently, the functional link between PGE2 suppression of glucose-stimulated insulin secretion (GSIS) and the EP3 receptor was confirmed using β-cell lines and isolated islets. It is hypothesized that increased PGE2 signaling through the EP3 receptor might be coincident with the development of diabetes and contribute to β-cell dysfunction. Therefore, EP3 receptor antagonists, may be an effective treatment for Type I and Type II Diabetes Mellitus, by relieving the inhibitory action of PGE2 to partially restore defective GSIS in diabetic patients. EP3 receptor antagonists may also be useful for the treatment of bladder over-activity, cerebrovascular disease, coronary artery disease, hypertension, neurodegenerative disorders, pain, premature labor, restenosis, thrombosis and colon cancer (KAWAMORI, T., et al., “Prostanoid receptors and colon carcinogenesis”, Carcinogenesis and Modification of Carcinogenesis (2005), pp 243-251.).
JIN, J., et al., in ACS Med. Chem. Lett., 2010, pp 316-320, Vol. 1 describe novel 3-oxazolidinedione-6-aryl pyridinones as potent, selective and orally active EP3 receptor antagonists. MORALES-RAMOS, A. I., et al., in Biororg & Med Chem Lett., 2011, pp 2806-2811, Vol. 21 describe structure-activity relationship studies of novel 3-oxazolidinedione-6-naphthyl-2-pyridinones as potent and orally available EP3 receptor antagonists.
BAHNCK, K., et al., in US Patent Publication 2016/0176851 A1 (Published Jun. 23, 2016) and BAHNCK, K., et al., in US Patent Publication 2015/0099782 A1 (Published Apr. 9, 2015) describe antagonists of prostaglandin EP3 receptor.